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Novel carboxy tetrahydropyrazolopyrazine compounds for the treatment of infectious diseases

a technology of pyrazolopyrazine and compound, which is applied in the field of new carboxy tetrahydropyrazolopyrazine compounds for the treatment of infectious diseases, can solve the problems of high adverse event frequency, long-term use of nucs, and viral genotypes that do not show good responses to interferon therapy

Active Publication Date: 2019-10-24
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to new compounds, their manufacture, and their use as medications. The compounds are designed to inhibit the action of hepatitis B virus (HBV) and treat or prevent infection. Specifically, the invention introduces new compounds that target the viral polymerase, an essential enzyme for the replication of the virus. These compounds can have a significant impact on the development of anti-HBV drugs and offer a promising tool for the treatment of HBV infection.

Problems solved by technology

Hepatitis B virus (HBV) infection is a major public health problem worldwide, roughly 30% of the world's population show serological evidence of current or past infection.
The major drawback of PEG-IFN is its high frequency of adverse events.
Some viral genotypes do not show good responses to interferon therapy.
Long-term use of NUCs, on the other hand, poses the risk of drug resistance.
The majority of currently treated patients fail to achieve this goal.

Method used

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  • Novel carboxy tetrahydropyrazolopyrazine compounds for the treatment of infectious diseases
  • Novel carboxy tetrahydropyrazolopyrazine compounds for the treatment of infectious diseases
  • Novel carboxy tetrahydropyrazolopyrazine compounds for the treatment of infectious diseases

Examples

Experimental program
Comparison scheme
Effect test

example 1

(2S)-1-[1-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-5-oxo-pyrrolidin-3-yl]pyrrolidine-2-carboxylic acid

[0145]

[0146]The title compound was prepared according to the following scheme:

Step 1: Preparation of methyl (2S)-1-(5-oxopyrrolidin-3-yl)pyrrolidine-2-carboxylate (Compound 1b)

[0147]A mixture of pyrrolidine-2,4-dione (compound 1a, 200 mg, 2.02 mmol), methyl (2S)-pyrrolidine-2-carboxylate (334 mg, 2.02 mmol) and Pd / C (100 mg) in MeOH (20 mL) was stirred at room temperature for 40 hours under 50 psi H2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated to give compound 1b (400 mg, crude) as a brown oil.

Step 2: Preparation of tert-butyl (6S)-3-[4-[(2S)-2-methoxycarbonylpyrrolidin-1-yl]-2-oxo-pyrrolidin-1-yl]-6-methyl-6,7-dihydro-4H-pyrazol[1,5-a]pyrazine-5-carboxylate (Compound 1c)

[0148]A mixture of methyl (2S)-1-(5-oxopyrrolidin-3-yl)pyrrolidine-2-carboxylate (compound 1b, 400 mg), tert-butyl (6S)-3-io...

example 2

(2S)-1-[(2S)-2-methyl-1-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-5-oxo-pyrrolidin-3-yl]pyrrolidine-2-carboxylic acid

[0151]

[0152]The title compound was prepared according to the following scheme:

Step 1: Preparation of tert-butyl (2S)-3-[(2S)-2-methoxycarbonylpyrrolidin-1-yl]-2-methyl-5-oxo-pyrrolidine-1-carboxylate (Compound 2b)

[0153]To the mixture of tert-butyl (2S)-2-methyl-3,5-dioxo-pyrrolidine-1-carboxylate (500 mg, 2.34 mmol, for its synthesis, refer to Hosseini, M. et al Org. Letters 2006, 8, 2103) in DCE (10 mL) was added methyl (2S)-pyrrolidine-2-carboxylate (395 mg, 2.81 mmol) and AcOH (5 drops), the reaction mixture was stirred for 5 hours at 40° C., then NaCNBH3 (294 mg, 4.68 mmol) was added. The reaction mixture was stirred at 40° C. for 12 hours and then diluted with EtOAc (100 mL), filtered, and the filtrate was concentrated, the residue was purified by column chromatography (PE / EtOAc=1 / 1) to give crude compound 2b ...

example 3

2-[Methyl-[1-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-5-oxo-pyrrolidin-3-yl]amino]acetic acid

[0159]

[0160]Example 3 was prepared in analogy to Example 1 by using methyl 2-(methylamino)acetate instead of methyl (2S)-pyrrolidine-2-carboxylate. Example 3 (10 mg) was obtained as a white solid. LCMS (M+H+): 480.9, 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.70-7.65 (m, 1H), 7.30-7.20 (m, 2H), 5.10-5.01 (m, 1H), 4.95-4.73 (m, 1H), 4.47 (d, J=17.1 Hz, 1H), 4.44-4.34 (m, 1H), 4.32-4.00 (m, 6H), 3.10-2.85 (m, 5H), 1.30-1.15 (m, 3H)

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Abstract

The present invention relates to compounds of the formula (I),or pharmaceutically acceptable salts, enantiomer or diastereomer thereof, wherein R1 to R3 are as described above. The compounds may be useful for the treatment or prophylaxis of hepatitis B virus infection.

Description

RELATED APPLICATIONS[0001]This application is a Continuation of International Application No. PCT / EP2017 / 067319, filed Jul. 11, 2017, claiming priority to Application No. PCT / CN2016 / 090036, filed Jul. 14, 2016 and Application No. PCT / CN2017 / 080438, filed Apr. 13, 2017, each of which are incorporated herein by reference in its entirety.[0002]The present invention relates to organic compounds useful for therapy and / or prophylaxis in a mammal, and in particular for treating hepatitis B virus infection, and their pharmaceutical activity, manufacture, pharmaceutical compositions containing them and their potential use as medicaments.FIELD OF THE INVENTION[0003]The present invention relates to compounds of the formula (I),or pharmaceutically acceptable salts, enantiomer or diastereomer thereof, wherein R1 to R4 are as described below. The compounds of this invention are useful for the treatment or prophylaxis of hepatitis B virus infection.[0004]Hepatitis B virus (HBV) infection is a majo...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D487/04A61P31/20C07D498/08
CPCC07D487/08C07D498/08A61P31/20C07D487/04A61P31/12
Inventor HU, TAISHANKOU, BUYULIU, HAIXIAZHANG, ZHISENZHOU, ZHENG
Owner F HOFFMANN LA ROCHE & CO AG
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